Nerve cells actively repress alternative cell fates, researchers find


A neural cell maintains its identity by actively suppressing the expression of genes associated with non-neuronal cell types, including skin, heart, lung, cartilage and liver, according to a study by researchers at the Stanford University School of Medicine.

 It does so with a powerful . “When this protein is missing, neural cells get a little confused,” said Marius Wernig, MD, associate professor of pathology. “They become less efficient at transmitting nerve signals and begin to express genes associated with other cell fates.”

The study marks the first identification of a near-global repressor that works to block many cell fates but one. It also suggests the possibility of a network of as-yet-unidentified master regulators specific to each cell type in the body.

“The concept of an inverse master regulator, one that represses many different developmental programs rather than activating a single program, is a unique way to control neuronal cell identity, and a completely new paradigm as to how cells maintain their throughout an organism’s lifetime,” Wernig said.

Because the protein, Myt1l, has been found to be mutated in people with autism, schizophrenia and major depression, the discovered mode of action may provide new opportunities for therapeutic intervention for these conditions, the researchers said.

Wernig is the senior author of the study, which will be published online April 5 in Nature. Postdoctoral scholars Moritz Mall, PhD, and Michael Kareta, PhD, are the lead authors.

Repressors

Myt1l is not the only protein known to repress certain cell fates. But most other known repressors specifically block only one type of developmental program, rather than many. For example, a well-known repressor called REST is known to block the neuronal pathway, but no others.

“Until now, researchers have focused only on identifying these types of single-lineage repressors,” said Wernig. “The concept of an ‘everything but’ repressor is entirely new.”

In 2010, Wernig showed that it is possible to convert skin into functional neurons over the course of three weeks by exposing them to a combination of just three proteins that are typically expressed in neurons. This “direct reprogramming” bypassed a step called induced pluripotency that many scientists had thought was necessary to transform one cell type into another.

 One of the proteins necessary to accomplish the transformation of skin to neurons was Myt1l. But until this study the researchers were unaware precisely how it functioned.

“Usually we think in terms about what regulatory programs need to be activated to direct a cell to a specific developmental state,” said Wernig. “So we were surprised when we took a closer look and saw that Myt1l was actually suppressing the expression of many genes.”

These genes, the researchers found, encoded proteins important for the development of lung, heart, liver, cartilage and other types of non-neuronal tissue. Furthermore, two of the proteins, Notch and Wnt, are known to actively block neurogenesis in the developing brain.

Blocking Myt1l expression in the brains of embryonic mice reduced the number of mature neurons that developed in the animals. Furthermore, knocking down Myt1l expression in mature neurons caused them to express lower-than-normal levels of neural-specific genes and to fire less readily in response to an electrical pulse.

‘A perfect team’

Wernig and his colleagues contrasted the effect of Myt1l with that of another protein called Ascl1, which is required to directly reprogram skin fibroblasts into neurons. Ascl1 is known to specifically induce the expression of neuronal genes in the fibroblasts.

“Together, these proteins work as a perfect team to funnel a developing cell, or a cell that is being reprogrammed, into the desired cell fate,” said Wernig. “It’s a beautiful scenario that both blocks the fibroblast program and promotes the neuronal program. My gut feeling would be that there are many more master repressors like Myt1l to be found for specific cell types, each of which would block all but one cell fate.”

Source:medicalxpress.com

Growing cartilage with a 3D printer..


A partnership between scientists at the University of Wollongong and St Vincent’s Hospital Melbourne has led to a breakthrough in tissue engineering, with researchers growing cartilage from stem cells to treat cancers, osteoarthritis and traumatic injury.

In work led by Associate Professor Damian Myers of St Vincent’s Hospital Melbourne – a node of the UOW-headquartered Australian Research Council Centre of Excellence for Electromaterials Science (ACES) – scaffolds fabricated on 3D printing equipment were used to grow cartilage over a 28-day period from stem cells that were extracted from tissue under the knee cap.

 

Professor Myers said this was the first time true cartilage had been grown, as compared to “fibrocartilage”, which does not work long-term.

“We are trying to create a tissue environment that can ‘self-repair’ over many years, meaning the repaired site will not deteriorate,” he said.

“It’s very exciting work, and we’ve done the hard yards to show that what we have cultured is what we want for use in surgery for cartilage repair.”

ACES Director Professor Gordon Wallace and his team developed customised fabrication equipment to deliver live cells inside a printed 3D structure. This cutting edge technology was utilised to deliver 3D printed scaffolds on which the cartilage was grown.

“ACES has established a biomedical 3D printing lab at St Vincent’s Hospital Melbourne in April this year. This has greatly accelerated progress by bringing clinicians and materials scientists face to face on a daily basis,” Professor Wallace said.

This research, which will soon move to pre-clinical trials to demonstrate repair of cartilage, is part of a wider limb regeneration project, involving Professor Wallace, Professor Mark Cook and Professor Peter Choong through the Aikenhead Centre for Medical Discovery. The aim is to eventually use a patient’s own stem cells to grow muscles, fat, bone and tendons.

Professor Wallace and his team are also working to develop custom-made 3D printed human organs.

“By 2025, it is feasible that we will be able to fabricate complete functional organs, tailored for an individual patient,” he said.

 

Source: http://www.sciencealert.com.au

 

 

Cartilage Gives Early Warning of Arthritis, Study Finds.


knee-osteoarthritisDamage to the tissue that cushions joints occurs even before people feel pain, research shows.

By Robert Preidt, HealthDay News

Exercise-related damage in cartilage can help identify people with the earliest stages of osteoarthritis, a new study reveals.

The findings could improve early detection of the painful joint disease and could also be used to improve methods of repairing damaged cartilage, said study senior author Alan Grodzinsky, of the Massachusetts Institute of Technology, and colleagues.

For the study, the researchers developed a method that identifies osteoarthritis-related changes that occur in cartilage in response to high-load activities such as running and jumping.

Cartilage is firm, rubbery tissue that cushions bones and keeps them from rubbing together. When osteoarthritis begins to develop, the ability of cartilage to resist physical-activity-related impact is reduced. This is now known to be due to the loss of molecules called glycosaminoglycans (GAGs)

Using their new system, the researchers found that GAG-depleted cartilage loses its ability to stiffen under the forces of high-load activities. GAG loss also caused an increase in the depletion of fluids from the cartilage, which likely reduces protection against the impact of high-load activities.

The findings show how GAG loss at the earliest disease stages reduces the ability of this tissue to withstand high-load activities, according to the study, which was published in the April 2 issue of theBiophysical Journal.

“This finding suggests that people with early degradation of cartilage, even before such changes would be felt as pain, should be careful of dynamic activities such as running or jumping,” Grodzinsky said in a journal news release.

Osteoarthritis affects about one-third of older adults and is the most common type of joint disorder.